GENO- structural chromosomal abnormalities Flashcards
what are the types of structural abnormalities
translocations - reciprocal, robertsonian inversion deletion duplication rings isochromosomes
what is meant by translocation structural abnormality
exchange of two segments between non-homologous chromosomes - between non-paired chromosomes
how does tetravalence occur
during meiosis - chromosomes want to align with homologous pair- if there has been swapping of material they no longer math and cannot align so form a tetravalent / quadrivalent
what happens when a tetravalent cell divides
when the cell divides it takes with them one half of the tetravalent structure - it will take a complete copy and a variant - when they are fertilised they will then end up with trisomy of part of the translocated part and monosomy of the other
what happen if division occurs in a way in which the gamete contains both the translocated / complete chromosomes
the individual is a balanced carrier
what are the consequences of reciprocal translocation
may lead to miscarriage
learning difficulties, physical disabilities
tend to be specific to each individual so exact risks and clinical features vary
what is Robertsonian translocation
involves just the acrocentric chromosomes (p arms)
the p arms get lost and the q arms of the chromosome join together
which are the acrocentric chromosomes
13,14,15,21,22,Y
can you be ‘normal’ with 45 chromosomes
yes - Robertsonian translocation - you can still have all the relevant genetic material
what do the p arms contain
RNA
which Robertsonian translocations are relatively common
13: 14
14: 21
21: 21 - downs syndrome - 100% risk
what is meant by NHEJ
non-homologous end joining
what is the purpose of NHEJ
DNA repair mechanism
double stranded DNA breaks
rejoins the chunk of broken DNA
what happens the NHEJ goes wrong
can join the broken chunk of DNA into another chromosome
creating derivative chromosomes
are derivative chromosomes a problem
not usually in a healthy individual as they usually have one copy of the complete chromosome which makes up for the broken one - this person is known as a balance translocation carrier
it can be a problem though depending on what chromosomes are involved
what is the Philadelphia chromosome
generated due to translocation between chr 9 and 22
chromosome 9 contains ABL which is a protooncogene - when its on chromosome 9 it is non-oncogenic
on chromosome 22 there is the BCR gene (prone to breaking)
translocation of ABL onto C22 creates a fusion gene which triggers oncogenic potential of ABL leading to leukaemia / myeloma
what are features of the outcomes of translocations
very difficult to predict
only have approximate probability of producing possible gametes
some unbalanced translations may lead to spontaneous abortion - early conception
some may lead to miscarriage later in conception
some may result in live-born baby with various problems
what is meant by terminal deletion
genes at the end of the telomere is lost
what is meant by interstitial deletion
genes in the middle of the telomere are lost and the ends are joined together - the greater the deletion the easier it is to detect and diagnose
explain what is meant by unequal crossing over
at myosis - alleles should align perfectly and then exchange genetic material (normal)
if they have misaligned you can get simultaneous deletions and duplications
end up with normal non-recombinants but also one copy with deletion and one with duplication
meaning an individual with this unequal crossing over will either be monosomic or have three copies
what are sources of sample for genetic testing
prenatal - invasive - amniocentesis (amniotic fluid), chorionic villus samples (placenta), cell free foetal DNA
post natal - blood, saliva
explain how structural abnormalities can be detected using stained metaphase chromosomes
most common
g banding - giemsa stain
can be seen under the microscope and detect large scale abnormalities
looks for aneuploidies, translocation and large deletions
explain how structural abnormalities can be detected using FISH
fluorescent in situ hybridisation - specific to parts of the genome
looks for aneuploidies, translocations and large deletions
traditional FISH - need to know what youre looking for
cultured cells - metaphase spread
fluorescent probe
what is spectral karyotyping
painting all the chromosomes so no need for a hypothesis of what is wrong before hand - compare what is different to what you expected
explain how structural abnormalities can be detected using array CGH
array comparative genomic hybridisation
for detection of sub-microscopic chromosomal abnormalities
patient DNA labelled green
control DNA labelled red
complete process
measure of fluorescent signals compare control and patient DNA
looks for microdeletions and duplications
explain how structural abnormalities can be detected using QF-PCR
interested in peaks - healthy individual = 2 same size peaks / single large peak
trisomy 2 peaks but one is twice size of other / 3 peaks
quick
looks for aneuploidies - have to know what youre looking for so know what microsatellites to target
NIPT/ NGS
non-invasive prenatal testing / next generation sequencing
NIPT- cell free foetal DNA
maternal blood sample
trisomy testing
NGS- high chance indicator for an invasive test
how do you detect microsatellites
isolate DNA from individual
design primers specific to flanking sequence
PCR amplification
gel electrophoresis
homozygotes - single product of a specific size
heterozygotes - two different sized products
